Effect of antidepressant drugs on the vmPFC-limbic circuitry

•We studied the neural activation patterns of three antidepressant drugs.•All three drugs increased cFos expression in the deep ventromedial prefrontal cortex.•Nucleus accumbens activation by desipramine was diminished upon vmPFC lesions.•The vmPFC may be a key target of antidepressants, relaying the drug effects to the rest of the limbic system.

Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.